Use of a pde 5 inhibitor for treating and preventing hypopigmentary disorders

ABSTRACT

The invention relates to the use of PDE5 inhibitors for treating and/or preventing hypopigmentary disorders.

CROSS REFERENCE TO PRIOR APPLICATION

The present application is a divisional of U.S. patent application Ser.No. 11/660,351, filed Jul. 5, 2007, which is a national phaseapplication of International Patent Application No. PCT/EP2005/007747,filed Jul. 15, 2005, which in turn claims priority from European PatentApplication No. 04019695.8 and U.S. Patent Application No. 60/603,069,both filed Aug. 19, 2004, all of which are incorporated by reference intheir entireties.

FIELD OF THE INVENTION

The invention relates to the use of PDE5 inhibitor, or of an isomerthereof, or of a pharmaceutically acceptable salt thereof for treatingand/or preventing hypopigmentary disorders. In particular, the inventionrelates to the use of Tadalafil and/or Sildenafil, its isomers andpharmaceutically acceptable salts for treating and/or preventinghypopigmentary disorders. The invention also relates to methods oftreatment and or prevention of hypopigmentary disorders by administeringPDE5 inhibitors.

BACKGROUND OF THE INVENTION

In the skin or hair, melanocytes are the sole source of the pigmentmelanin. Melanin is synthesized within the melanocytes and latertransferred to the surrounding keratinocytes. The colour of the skin isdetermined to a large extent by the amount and type of melanin withinthe epidermis. In general dysfunction of the melanocytes or the loss ofthe melanocytes itself leads to loss of pigmentation. The mechanisms forthe destruction of melanocytes are likely to be multiple and complex,possibly a composite of several normal processes influencing melanocytefunction, proliferation and/or survival. Also the pathomechanism ofhyperpigmentary disorders is largely unclear.

Vitiligo, for example is a pigmentation disorder afflicting up to 2% ofthe worldwide population. It is a specific type of leukoderma manifestedcharacteristically by depigmentation of the epidermis, best described asan acquired, progressive disorder that selectively destroys some or allmelanocytes. The vitiligo disease is characterized by milky whitemacules on the skin, either due to missing melanin pigment or tocomplete absence of melanocytes in the dermo-epidermal junction ofvitiligo areas. Vitiligo tends to be progressive throughout the life ofaffected individuals. Other disorders of hypopigmentation that arecaused by a defect in melanin production or transfer include theChediak-Higashi syndrome, Hermansky-Pudlak syndrome, the Waardenburgsyndromes I-IV, the Angelman and Prader-Willi syndrome. Albinism insteadis characterized by genetic defects that impede the synthesis ofmelanin. Piebaldism is characterized by the absence of melanin at birthdue to a deficiency of melanocytes. During embryogenesis melanocytesfail to complete their migration from the neural crest to the epidermis.In vitiligo some melanocytes can be found in epidermis of early lesionsthat are only partially depigmented. In late lesions that were totallydepigmented, there is complete absence of melanocytes. Also, there is alack of knowledge about the pathophysiology and mechanisms underlyingmost pigmentary disorders.

At the moment there are still several hypotheses to explain the possiblecauses of vitiligo:

-   1) Autoimmune disease: Specific autoantibodies to melanocyte cell    surface antigens are present in the circulation of most patients    with vitiligo. These antibodies are unusual in persons with    nonpigmentary skin diseases. Vitiligo antibodies are shown to have    the functional capacity to kill pigment cells in vitro and can do so    by two different mechanisms: complement-dependent cytotoxicity and    antibody-dependent cellular cytotoxicity.-   2) Self-destruction of melanocytes as a consequence of aberrant    melanin biosynthesis: The autocytotoxic hypothesis is based on the    observation that phenol and some of its derivatives are capable of    killing pigment cells. Tyrosine, the substrate of the tyrosinase is    itself a phenol derivative, is oxidized into melanin via a complex    series of oxidative reactions. Some intermediates are capable of    forming radicals. It is thought that melanin synthesis is confined    within the melanosome to prevent these melanin precursors from    diffusing into the cell where they might disrupt essential metabolic    pathways.-   3) Overproduction of neurotransmitters leading to death of    melanocytes: Melanocytes are neural crest derived cells. A    dysfunction of nervous function might be involved in the    pathogenesis of vitiligo as shown by an altered balance of    neuropeptides in vitiliginous skin. Neuropeptides are able to induce    melanocyte dendricity and participate in the regulation of cell    substrate adhesion, cell motility and shape. Neuropeptides may also    regulate melanin synthesis or affect melanosomal transfer to    surrounding keratinocytes.-   4) More recently, also viral infections as well as oxidative stress    and hormonal causes are discussed to be involved in the disease    formation.-   5) Although the pathogenesis of vitiligo is still not known, there    is a genetic predisposition, demonstrated by the fact, that 40% of    vitiligo patients have a positive family history for this disease.-   6) A combination of some or all of above theories

Currently, no satisfying treatments exist for pigmentary disorders. Forexample, at present, there is no specific therapy for Vitiligo availablewithout side effects and no innovative therapeutic programs are underdevelopment. No single therapy predictably produces good results in allpatients and the responses are highly variable: systemicphotochemotherapy (PUVA) gives satisfactory results only in some earlydisease states, however, treatment is time-consuming and has a high riskof developing cancer after prolonged treatment. Other therapies comprisesystemic steroids, e.g. prednisone, hydrocortisone or triamcinolone,which however are also not suitable for prolonged treatment. In somecases, transplantation of skin has given positive results. In extremecases, where the depigmented area has become very large, total chemicaldepigmentation of the skin is performed to achieve a homogeneouscoloring of the skin.

Similarly, no specific and satisfactory treatment exists for Pityriasisalba, a common hypopigmented dermatitis that occurs primarily inschool-aged children. Usually this disorder is left untreated astreatments with corticosteroids or retinoic acid or PUVA treatment arenot very efficient.

Some pigmentary disorders, like vitiligo, have only skin manifestationslimited to the pigmentation alterations. However, these disordersnevertheless pose severe psychological problems to the patients, as thesharp borders of depigmented areas are readily apparent to otherpersons, especially when occurring in the face. Vitiligo can bedisfiguring and stigmatising, thereby causing significant psychologicalproblems due to reduced social acceptance. Also, vitiligo usuallypersists for the whole life.

There is therefore a need for a specific treatment of hypopigmentarydisorders, preferably vitiligo.

BRIEF DESCRIPTION OF THE DRAWINGS

Further aspects of the present invention will become evident by thefigures and the following examples which are given to merely illustratethe invention, not to limit the same.

FIG. 1 shows the influence of Sildenafil on dendrite formation inmelanocytes in a melanocyte dendrite outgrowth assay.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly it was found, that PDE5 inhibitors are suitable for thetreatment and prevention of hypopigmentary disorders, especiallyvitiligo. Especially preferred are the PDE5 inhibitors Sildenafil,Tadalafil and Vardenafil, in particular Tadalafil and Sildenafil.

Phosphodiesterase 5 or PDE5 is one member of a superfamily of cyclicnucleotide hydrolysing enzymes that specifically cleaves cyclicguanosine monophosphate (cGMP) which is a second messenger. PDE5inhibitors have originally been proposed to be useful in the treatmentof hypertension and angina, however, the main focus is now their use inthe treatment of erectile dysfunction. Other suggested activities ofPDE5 inhibitors are reversal of gastric emptying, lowering bloodpressure and pulmonary hypertension (see Rotella D. P., 2001, Drugs ofthe Future, 26: 153-162). It has never been proposed that the compoundsof the invention are useful in the treatment and/or prevention ofhypopigmentary disorders.

A range of PDE5 inhibitors with proven or suggested potential for use asmedicine are known up to know. Such PDE5 inhibitors, which can be usedaccording to the invention and which are included by reference are:

Dihydrotriazolohydropurinone derivatives which are disclosed in WO01/07441;purinone derivatives which are described in WO 94/00453;Pyrazolo[3,4-d]pyrimidinine-4-one derivatives which are described in EP0636626; WO 96/28429; WO 96/28448; WO 94/28902; U.S. Pat. No. 5,294,612and EP 0995751;1,6-Dihydro-7H-pyrazolo-[3,4-d]pyrimidin-4-one derivatives which aredescribed in EP 0201188; WO 88/00192; EP 0995750; EP 1057829; EP1092720; WO 01/127101; WO 01/27112; WO 01/27113 and WO 00/27848;Imidazotriazinone derivatives which are described in WO 99/24433, WO99/67244; and EP 1092719;Imidazoquinazolinone derivatives which are described in WO 99/64004;Pyrazolopyridopyrimidine derivatives which are described in Krupinski etal., 2001, Bioorg. Med. Chem. Lett., 11: 2461-2464Pyrrolopyrimidinone derivatives which are disclosed in WO 01/60825;Quinazolinone and Pyridopyrimidone derivatives which are disclosed in WO93/12095 and WO 94/05661 and JP 8104679; JP 07330777 and JP 07267961;Fused pyrimidine derivatives which are disclosed in Lee et al., 1995, J.Med. Chem., 38: 3547-3557, WO 98/06722, WO 02/26745; DE 19752952; WO99/55708; DE 19943815; DE 19944604; Jonas et al., 2002, Chem. Abstr.136: 85819; WO 99/43674; WO 00/59912; WO 98/17668; WO 02/18389; U.S.Pat. No. 5,436,233; EP 728759; U.S. Pat. No. 5,525,604; WO 93/07124; WO96/26940; WO 95/06648; WO 98/08848; WO 99/43679; WO 99/43674; DE19942474; WO 01/12608; WO 00/15222 and WO 02/20489;Pyrimidine derivatives which are described in WO 01/19802; WO 01/83460;WO 98/23597; EP 0640599, WO 96/05176, WO 98/07430, WO 99/42452, WO01/05770 and WO 00/56719;Isoquinoline derivatives which are disclosed in WO 98/38168, WO00/12503; EP 128462 and JP 12281654;Hexahydropyrazino-pyrido-indole-1,4-dione derivatives which aredisclosed in WO 95/19978, WO 97/03675, U.S. Pat. No. 6,143,746, WO96/32003, WO 95/19978, WO 97/03985, WO 01/80860, WO 01/808686, WO00/66114, WO 02/10166, WO 02/28858, WO 97/43287, U.S. Pat. No.6,306,870, U.S. Pat. No. 6,043,252 and WO 01/87038;Anthranilic acid diamide derivatives which are disclosed in WO 95/18097and WO 99/54284,Pyridocarbazolone derivatives which are described in WO 98/53819, WO99/26946, WO 00/32195 and WO 99/28319;Indole and Benzimidazole derivatives which are disclosed in WO 96/32379,WO 99/51574, WO 98/15530, WO 97/24334, WO 99/00373, WO 00/39099, WO99/00373, WO 00/34277, JP 101824549, WO 97/03070, WO 99/00350, WO00/39099, WO 00/39097, WO 99/0372 and WO 99/21831;Pyrazoloquinoline and pyrazolopyridine derivatives which are disclosedin U.S. Pat. No. 5,488,055 and WO 96/28159;Imidazopyridopyrazinones which are disclosed in WO 00/43392 and DE19510965;Quinazolinedione phtalimide derivatives which are disclosed in WO01/44228 and WO 00/20412;Cyclobutendione derivatives which are disclosed in WO 00/51973, WO00/63170, WO 00/63160 and WO 94/29277;Dual PDE1/5 inhibitors which are disclosed in WO 91/19717 and WO97/19947(see Haning et al., Progress in Medicinal Chemistry, 2003, 41: 249-306for a review on PDE 5 inhibitors).

PDE5 inhibitors for the use according to the present invention include:the pyrazolo[4,3-d]pyrimidin-7-ones disclosed in EP-A-0463756,especially Sildenafil and salts and hydrates thereof; thepyrazolo[4,3-d]pyrimidin-7-ones disclosed in EP-A-0526004; thepyrazolo[4,3-d]pyrimidin-7-ones disclosed in published internationalpatent application WO 93/06104; the isomericpyrazolo[3,4-d]pyrimidin-4-ones disclosed in published internationalpatent application WO 93/07149; the quinazolin-4-ones disclosed inpublished international patent application WO 93/12095; thepyrido[3,2-d]pyrimidin-4-ones disclosed in published internationalpatent application WO 94/05661; the purin-6-ones disclosed in publishedinternational patent application WO 94/00453; thepyrazolo[4,3-d]pyrimidin-7-ones disclosed in published internationalpatent application WO 98/49166; the pyrazolo[4,3-d]pyrimidin-7-onesdisclosed in published international patent application WO 99/54333; thepyrazolo[4,3-d]pyrimidin-4-ones disclosed in EP-A-0995751; thepyrazolo[4,3-d]pyrimidin-7-ones disclosed in published internationalpatent application WO 00/24745; the compounds disclosed in publishedinternational application WO95/19978; the compounds disclosed inpublished international application WO 99/24433 and the compoundsdisclosed in published international application WO 93/07124.

It is to be understood that the contents of the above published patentapplications, and in particular the general formulae and exemplifiedcompounds therein are incorporated herein in their entirety by referencethereto.

PDE5 inhibitors which may be used according to the invention include3-ethyl[2-(4-morpholinylmethyl)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]quinazoline-2-thione;1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole carboxamide;9-bromo-2-(3-hydroxypropoxy)-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]-carbazol-4-one;4-(1,3-benzodioxol-5-ylmethylamino)-2-(1-imidazolyl)-6-methylthieno[2,3-d]pyrimidine;6-(2-isopropyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-yl)-5-methyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one;5-(4-methylbenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro[1,2,3]triazolo[4,5-d]pyrimidin-7-one;3-(1-methyl-4-phenylbutyl)-5-pyridin-4-ylmethyl-3,6-dihydro[1,2,3]triazolo[4,5-d]pyrimidin-7-one;5-(4-bromobenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro[1,2,3]-triazolo[4,5-d]pyrimidin-7-one;5-benzyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]-triazolo[4,5d]pyrimidin-7-one;5-(3,4-dimethoxybenzyl) (I-methylphenylbutyl)-3,6-dihydro-[1,2,3]-triazolo-[4,5d]pyrimidin-7-one;5-(3,4-dichlorobenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]-triazolo[4,5d]pyrimidin-7-one;5-biphenyl-4-ylmethyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]-triazolo[4,5d]pyrimidin-7-one;5-(4-aminobenzyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]-triazolo[4,5-d]pyrimidin-7-one;5-(hydroxyphenylmethyl)-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]-triazolo-[4,5d]pyrimidin-7-one;5-benzo[1,3]-dioxol-5-ylmethyl-3-[1-methyl-4-phenylbutyl]-3,6-dihydro[1,2,3]-triazolo[4,5-d]pyrimidin-7-one;N-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]-triazolo-[4,5-d]pyrimidin-5-ylmethyl]phenylacetamide;5-benzoyl-3-(1-methyl-4-phenylbutyl)-3,6-dihydro-[1,2,3]triazolo[4,5-d]-pyrimidin-7-one;3-(1-methyl-4-phenylbutyl)-5-[4-(morpholine-4-sulphinyl)benzyl]-3,6-dihydro[1,2,3]triazolo[4,5-d]pyrimidin-7-one;3-(1-methyl-4-phenylbutyl)-5-[3-(morpholine-4-sulphonyl)benzyl]-3,6-dihydro[1,2,3]triazolo[4,5-d]pyrimidin-7-one;N-methyl-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]-triazolo-[4,5-d]pyrimidin-5-ylmethyl]-benzenesulphonamide;N-(2-dimethylaminoethyl)-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylmethyl]benzenesulphonamide;N-(2-hydroxyethyl)-4-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylmethyl]benzenesulphonamide;ethyl1-[3-[3-(1-methyl-4-phenylbutyl)-7-oxo-6,7-dihydro-3H-[1,2,3]-triazolo-[4,5-d]pyrimidin-5-ylmethyl]benzenesulphonyl]piperidinecarboxylate;3-(1-methyl-4-phenylbutyl)-5-[4-(4-methylpiperazin-1-sulphonyl)benzyl]-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one;5-benzo[1,3]dioxol-5-ylmethyl-3-[1-ethyl-heptyl]-3,6-dihydro-[1,2,3]-triazolo[4,5-d]pyrimidin-7-one;3-[1-(1-hydroxyethyl)-4-phenylbutyl]-5-[4-(morpholine-4-sulphonyl)benzyl]-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one;5-[6-fluoro-1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol;1-benzyl-6-fluoro-3-[5-(hydroxymethyl)furan-2-yl]-1H-indazole;2-(1H-imidazol-1-yl)-6-methoxy-4-(2-methoxyethylamino)quinazoline;1-[[3-(7,8-dihydro-8-oxo-1H-imidazo[4,5-g]quinazolin-6-yl)-4-propoxyphenyl]sulphonyl]-4-methylpiperazine;4-(3-chloro-4-methoxybenzylamino)-1-(4-hydroxypiperidin-1-yl)phthalazine-6-carbonitrile;1-[6-chloro-4-(3,4-methylendioxybenzylamino)quinazolin-2-yl]piperidin-4-carboxylicacid; (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-12,3,4,6,7,12,12a-octa-hydropyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione(Tadalafil);(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione;4-ethoxy-2-phenylcycloheptylimidazole;(6-bromo-3-methoxymethylimidazo[1,2-a]pyrazin-8-yl)methylamine;8-[(phenylmethyl)thio]-4-(1-morpholinyl)-2-(1-piperazinyl)pyrimidino[4,5-d]pyrimidine;(+)-cis-5-methyl-2-[4-(trifluoromethyl)benzyl]-3,4,5,6a,7,8,9-octahydrocyclopent[4,5]imidazo[2,1-b]purin-4-one;cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-b]purin-4-one;5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(Sildenafil);1-[[3(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine;2-(2-propoxyphenyl)purin-6(1H)-one;2-(2-propoxyphenyl)-1,7-dihydro-5H-purin-6-one; methyl2-(2-methylpyridin-4-ylmethyl)-1-oxo-8-(2-pyrimidinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-[2,7]naphthyridin-3-carboxylate;methyl2-(4-aminophenyl)-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-1,2-dihydroisoquinoline-3-carboxylate;2-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)phenyl]-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one(Vardenafil);3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2-(1H)-quinolinone(vesnarinone);1-cyclopentyl-3-methyl-6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one;1-cyclopentyl-6-(3-ethoxy-4-pyridin-8-azapurin-6-one;3,6-dihydro-5-(o-propoxyphenyl)-7H-[1,2,3]triazolo[4,5-d]pyrimidin-7-oneand 4-methyl-5-(4-pyridinyl)thiazole-2-carboxamide and thepharmacologically acceptable salts of these compounds.

Other PDE5 inhibitors useful in conjunction with the present inventioninclude:

-   4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)-propoxy]-3(2H)pyridazinone;-   1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinozolinyl]-4-piperidine-carboxylic    acid, monosodium salt;-   (+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopent-4,5]imidazo[2,1-b]purin-4(3H)one;-   furazlocillin;-   cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]-imidazo[2,1-b]purin-4-one;-   3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;    3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;-   4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)-3-(2H)pyridazinone;-   1-methyl-5(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;-   1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4-piperidinecarboxylic    acid, monosodium salt;-   Pharmaprojects No. 4516 (Glaxo Wellcome); Pharmaprojects No. 5051    (Bayer);-   Pharmaprojects No. 5064 (Kyowa Hakko; see WO 96/26940);-   Pharmaprojects No. 5069 (Schering Plough); GF-196960 (Glaxo    Wellcome); Bay-38-3045 & 38-9456 (Bayer);-   (S)-2-(2-Hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-pyrimidinylmethyl)carbamoyl]pyrimidine;-   DA-8159 (Benzenesulfonamide,    3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-4-propoxy-);-   EMD-221829;-   UK 357903 (piperazine,    1-ethyl-4-[[5-[3-ethyl-4,7-dihydro-7-oxo-2-(2-pyridinylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-6-(2-methoxyethoxy)-3-pyridinyl]sulfonyl]-);-   UK 114542.

Preferred PDE5 inhibitors include:

BMS-341400 which has the following structure:

BMS-281384 which has the following structure:

BMS-263504, LAS-34179, LAS-30902, LAS-34837, AWD-12-250,

OSI-461 (CAS RN No. 227619-96-7) which has the following structure:

Exisulind which has the following structure:

Sophoflavescenol which has the following structure:

DA-8159 (Benzenesulfonamide,3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-4-propoxy-);E-8010 (6-Phthalazinecarbonitrile,4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-1-(4-hydroxy-1-piperidinyl)-and its monohydrochloride salt);E4010([4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy)piperidino]-6-phthalazinecarbonitrile monohydrochloride);FR-181074; FR-226807 (Benzamide,N-[(3,4-dimethoxyphenyl)methyl]-2-[[(1R)-2-hydroxy-1-methylethyl]amino]-5-nitro-);FR-189318;FR-229934, which has the following structure:

DMPPO, GF-248(1-Methyl-5-(5-morpholinoacetyl-2-propoxyphenyl)-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one),KF-31327 (3-Ethyl-8-[2-(4-hydroxymethylpiperidino)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]quinazoline-2-thionedihydrochloride); EMD-82639; EMR-62203; NCX-911 (Sildenafil nitrate);NM-702 which has the following structure:

QAD-171A which has the following structure:

OPC-35564 which has the following structure:

UK-114542; UK-357903; UK-369003;

UK-83405 which has the following structure:

UK-114502; SR-265579 (4H-Pyrazolo[3,4-d]pyrimidin-4-one,1-cyclopentyl-6-(3-ethoxy-4-pyridinyl)-3-ethyl-1,3a-dihydro-);SCH-446132 which has the following structure:

and which is disclosed in WO 00/224698;Sch-51866(Cyclopent[4,5]imidazo[2,1-b]purin-4(1H)-one,5,6a,7,8,9,9a-hexahydro-5-methyl-2-[[4-(trifluoromethyl)phenyl]methyl]-,(6aR,9aS)-rel-) which has the following structure:

Sch-59498; SK-3530, SB-96231(2-(2-Propoxyphenyl)-1,7-dihydro-6-purinone; SKF-96231); WIN-65579(4H-Pyrazolo[3,4-d]pyrimidin-4-one,1-cyclopentyl-6-(3-ethoxy-4-pyridinyl)-3-ethyl-1,7-dihydro-); Avanafil(5-Pyrimidinecarboxamide,4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-2-[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-);T-0156 which has the following structure:

T-1032 (3-Isoquinolinecarboxylic acid,2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-,methyl ester, sulfate); YC-1 (2-Furanmethanol,5-[1-(phenylmethyl)-1H-indazol-3-yl]-)and salts and esters thereof, or, where the compound is already a salt,a different salt thereof.

Further preferred PDE5 inhibitors for the use according to the presentinvention include:

-   5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (Sildenafil) also known as    1-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4-methylpiperazine    ((see EP-A-0463756); see Example 1 of the present invention)-   5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see EP-A-0526004);-   3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO98/49166);-   3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO99/54333);-   (+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    also known as    3-ethyl-5-{5-[4-ethylpiperazin-1-ylsulphonyl]-2-([(1R)-2-methoxy-1-methylethyl]oxy)pyridin-3-yl}-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (see WO99/54333);-   5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    also known as    1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulphonyl}-4-ethylpiperazine;-   5-[2-iso-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylpiperidin-4-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;-   5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;-   5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;-   5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;-   (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione    (Tadalafil; IC-351; see Example 2 of the present application), i.e.    the compound of examples 78 and 95 of published international    application WO95/19978, as well as the compound of examples 1, 3, 7    and 8 of WO95/19978;-   2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one    (Vardenafil) also known as    1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulphonyl]-4-ethylpiperazine,    i.e. the compound of examples 20, 19, 337 and 336 of published    international application WO99/24433; and-   the compound of example 11 of published international application    WO93/07124 (EISAI); and-   compounds 3 and 14 from Rotella D P, J. Med. Chem., 2000, 43, 1257.

A particularly preferred PDE5 inhibitor of the present invention isSildenafil, which has the following structure:

or a pharmaceutically acceptable salt thereof, in particular the citratesalt.

Alternative names for Sildenafil are5-[2-Ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-oneand1-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methyl-piperazine.The synthesis of the compound is well known for a skilled person and forexample described in described in EP 0 463 756B1. The CAS No. is139755-83-2.

The preferred salt of Sildenafil useable according to the invention isSildenafil citrate.Another particularly preferred PDE5 inhibitor of the present inventionis Tadalafil, which has the following structure:

Alternative names for Tadalafil arePyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione,6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-and Pyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione,6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R-trans)-and(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dioneand Cialis; GF 196960; IC 351 and ICOS 351. The synthesis of thecompound is well known for a skilled person and for example described indescribed in WO 95/19978. The CAS Reg. No is 171596-29-5.

The suitability of any particular PDE5 inhibitor can be readilydetermined by evaluation of its potency and selectivity using literaturemethods followed by evaluation of its toxicity, absorption, metabolism,pharmacokinetics, etc in accordance with standard pharmaceuticalpractice.

Preferably, the PDE5 inhibitors have an IC₅₀ at less than 100 nanomolar,more preferably, at less than 50 nanomolar, more preferably still atless than 10 nanomolar.

IC₅₀ values for the PDE5 inhibitors may be determined using establishedliterature methodology, for example as described in EP0463756 andEP0526004.

Preferably the PDE5 inhibitors used in the invention are selective forthe PDE5 enzyme. Preferably they are selective over PDE3, morepreferably over PDE3 and PDE4. Preferably, the PDE5 inhibitors of theinvention have a selectivity ratio greater than 100, more preferablygreater than 300, over PDE3 and more preferably over PDE3 and PDE4. Theterm “to have a selectivity ratio for enzyme z greater than x . . . overenzyme y”, as used herein, is meant to designate that acompound/substance characterised by such term have an x-times greaterpreference for enzyme z than for enzyme y.

Selectivity ratios may readily be determined by the skilled person. IC₅₀values for the PDE3 and PDE4 enzyme may be determined using establishedliterature methodology, see S. A. Ballard et al, Journal of Urology,1998, vol. 159, pages 2164-2171.

Surprisingly, the PDE5 inhibitors, such as Sildenafil and Tadalafil, canbe used to treat hypopigmentary disorders, especially vitiligo. Thepresent invention therefore relates to the use of a PDE5 inhibitor forthe manufacture of a medicament for treating and/or preventinghypopigmentary disorders, especially vitiligo. Furthermore the presentinvention relates to a method of treating and/or preventinghypopigmentary disorders, especially vitiligo comprising administeringto a mammal a PDE5 inhibitor.

Surprisingly it was found that compounds according to formula (I):

or isomers thereof or pharmaceutically acceptable salts thereof, areuseful in the treatment and prevention of hypopigmentary disorders,especially vitiligo.

Moreover it was surprisingly found that a PDE5 inhibitor, especiallySildenafil, is especially suitable for the treatment and prevention ofhypopigmentary diseases which have an inflammatory and/or autoimmunecomponent and/or in which T cell activation and proliferation plays arole, especially preferred vitiligo. Such inflammatory and/or autoimmunecomponent may form part of the hypopigmentary disease or may be inaddition thereto.

The present invention therefore relates to the use of a compoundaccording to formula

or an isomer thereof, or a pharmaceutically acceptable salt thereof, forthe manufacture of a medicament for treating and/or preventinghypopigmentary disorders, especially vitiligo.

In a preferred embodiment, the compound is Sildenafil or apharmaceutically acceptable salt thereof, in particular the citratesalt.

Surprisingly it was found that compounds according to formula (II)

or isomers thereof or pharmaceutically acceptable salts thereof, areuseful in the treatment and prevention of hypopigmentary disorders,especially vitiligo.

Moreover it was surprisingly found that a PDE5 inhibitor, especiallyTadalafil is especially suitable for the treatment and prevention ofhypopigmentary diseases which have an inflammatory and/or autoimmunecomponent and/or in which T cell activation and proliferation plays arole, especially preferred vitiligo. Such inflammatory and/or autoimmunecomponent may form part of the hypopigmentary disease or may be inaddition thereto.

The present invention therefore relates to the use of a compoundaccording to formula (II):

or an isomer thereof, or a pharmaceutically acceptable salt thereof, forthe manufacture of a medicament for treating and/or preventinghypopigmentary disorders, especially vitiligo. In a preferredembodiment, the compound is Tadalafil or a pharmaceutically acceptablesalt thereof.

The invention also relates to a method of treating and/or preventinghypopigmentary disorders, especially vitiligo, comprising administeringto a mammal a compound according to formula (I):

or an isomer thereof, or a pharmaceutically acceptable salt thereof, inparticular the citrate salt.

In an even more preferred embodiment, the compound is selected fromSildenafil or a pharmaceutically acceptable salt thereof, in particularthe citrate salt.

The invention also relates to a method of treating and/or preventinghypopigmentary disorders, especially vitiligo, comprising administeringto a mammal a compound according to formula (II):

or an isomer thereof or a pharmaceutically acceptable salt thereof.

In an even more preferred embodiment, the compound is selected fromTadalafil or a pharmaceutically acceptable salt thereof.

In one embodiment, the hypopigmentary disorder has an inflammatoryand/or an autoimmune component. Preferably the hypopigmentary disorderis selected from albinism, vitiligo, postinflammatory hypopigmentation,piebaldism, Pityariasis alba, Hypomelanoses, Leukodermas,hypopigmentation occurring e.g. after externally induced peels, e.g.chemical peels, e.g. with phenol, or laser or cryo-surgery of the skin,Chediak-Higashi syndrome, Hermansky-Pudlak syndrome, the Angelman andPrader-Willi syndrome, wherein, more preferably, the hypopigmentarydisorder is a disorder in which T cell activation and proliferationplays a role, and which hypopigmentary disorder is more preferablyselected from post-inflammatory hypopigmentation and vitiligo. In themost preferred embodiment, the hypopigmentary disorder is vitiligo.

Methods of production of the compounds according to the presentinvention are well known to someone skilled in the art, and aredescribed e.g. in, the contents of the documents cited above which arehereby incorporated by reference.

Preferably, the medicament according to the present invention isprepared in a form suitable for topical use, preferably in form of anointment, a gel, a plaster, an emulsion, a lotion, a foam, a cream, acream of a mixed phase or amphiphilic emulsion system(oil/water-water/oil mixed phase), a liposome, a transfersome, a pasteor a powder, or a solution or suspension.

In one embodiment, the compound is applied topically or systemically orvia a combination of the two routes, preferably topically.

The objects of the present invention are also solved by a compositioncomprising a PDE5 inhibitor useable according to the invention and oneor more further active ingredients suitable for the treatment and/orprevention of hypopigmentary disorders. Preferably, such composition isused as a pharmaceutical.

In a preferred embodiment the objects of the present invention aresolved by a composition comprising a compound according to formula (I)

or an isomer thereof, or a pharmaceutically acceptable salt thereof, andone or more further active ingredients suitable for the treatment and/orprevention of hypopigmentary disorders.

In a preferred embodiment the objects of the present invention are alsosolved by a composition comprising a compound according to formula (II)

or an isomer thereof, or a pharmaceutically acceptable salt thereof, andone or more further active ingredients suitable for the treatment and/orprevention of hypopigmentary disorders. Preferably, such composition isused as a pharmaceutical.

In one embodiment, the further active ingredient is selected from thegroup consisting of cyclosporin A, cyclosporin G, cyclosporin B,cyclosporin C, cyclosporin D, dihydro-cyclosporin D, cyclosporin E,cyclosporin F, cyclosporin H, cyclosporin I, ASM-240, pimecrolimus,tacrolimus, 13-desmethyl-derivatives of tacrolimus (L-685487), L-683519and/or 17-ethyl-derivatives of tacrolimus, preferably pimecrolimus,tacrolimus, or cyclosporin A, most preferably tacrolimus; steroids, inparticular betamethasone, betamethasone-17-valerate, fluocinolone,triamcinolone, triamcinolone acetonide, clobetasol, clobetasolpropionate, halobetasol, hydrocortisone, cortisone, desonide,prednisolone, paramethasone, methylprednisolone, dexamethasone,deflazacort; vitamin D analogues, in particular calcipotriol;pseudocatalase; levamisole, fluorouracil; alpha-MSH; clofazimine;thiambutosine BP; chloroquine; penicillamine; tar; minoxidil; inosiplex;mechlorethamine; cyclophosphamide; anapsos; antioxidants like Gingkobiloba, canthaxanthine, beta-carotene, alpha-tocopherol, a combinationof alpha-tocopherol ubiquinone seleno-methionine and methionine;pentoxifylline; vitamins and trace elements, in particular vitamin B12,folic acid, vitamin C, vitamin E, copper salts, human placental extract,khellin and phenylalanine.

Preferably, the composition according to the present invention isformulated for topical use, more preferably in form of an ointment, agel, a plaster, an emulsion, a lotion, a foam, a cream, a cream of amixed phase or amphiphilic emulsion system (oil/water-water/oil mixedphase), a liposome, a transfersome, a paste or a powder, or a solutionor suspension.

The objects of the present invention are furthermore solved by the useof the composition according to the present invention for themanufacture of a medicament for the treatment and/or prevention ofhypopigmentary disorders.

Hypopigmentary Disorders

Hypopigmentary disorders according to the present invention arenon-malignant disorders of the skin in mammals, including humans whichare characterized by a decrease in pigmentation of the skin compared tohealthy individuals. Such decrease in pigmentation may occur locally, ase.g. in mild forms of vitiligo, or may affect the whole skin. Suchdecrease in pigmentation may result in total loss of pigmentation, ase.g. in affected skin areas of vitiligo patients, or may result in“lighter” but still pigmented skin as in Pityriasis alba. In someembodiments, the hypopigmentary disorders, according to the presentinvention, have an inflammatory and/or an autoimmune component. As usedherein, the term “having an inflammatory component” is meant todesignate any condition which is accompanied locally or temporally withsyndromes characteristic of an inflammatory reaction, such as theinduction of certain cytokines, in particular soluble IL-2R (sIL-2R),IL-6 and IL-8, and increased levels of inflammatory cells, in particularT-cells and macrophages, at sites of lesions or around lesions. Suchinflammatory and/or an autoimmune component may form part of thehypopigmentary disorder or may be in addition thereto.

The term “accompanied temporally” may mean that the inflammatorycomponent precedes the hypopigmentary disorder, is concomitant therewithor follows it.

The term “autoimmune component” in an organism is meant to designate anycondition which is characterized by a reaction of the organism's ownimmune system against the organism itself or tissues or cells or othercomponents thereof. An example of such a reaction is the production ofauto-antibodies which are antibodies that are directed at some of anorganism's own tissues or cells or other body components.

Examples of hypopigmentary disorders are, but not limited to, albinism,vitiligo, postinflammatory hypopigmentation, piebaldism, Pityariasisalba, Hypomelanoses, Leukodermas, hypopigmentation occurring e.g. afterexternally induced peels, e.g. chemical peels with phenol, or laser orcryo-surgery of the skin, Chediak-Higashi syndrome, Hermansky-Pudlaksyndrome, the Angelman and Prader-Willi syndrome. An especiallypreferred hypopigmentary disorder of the present invention is vitiligo.

Examples of hypopigmentary disorders in which T cell activation andproliferation plays a role are postinflammatory hypopigmentation andvitiligo, preferably vitiligo.

Treatment according to the present invention relates to the complete orpartial healing of the hypopigmentary disorder in mammals, includinghumans as well as to the stop or slowing-down of the progression of ahypopigmentary disorder. Also, the compounds of the present inventionare suitable for the prevention of a hypopigmentary disorder in mammals,including humans.

Treatment of vitiligo according to the present invention relates to thecomplete or partial healing of the disorder vitiligo; i.e. complete orpartial repigmentation of existing white macules on vitiligo patients,as well as to the stop or slowing-down of the extension of the whitemacule areas on vitiligo patients. Prevention of vitiligo according tothe present invention relates to the prevention of occurrence ofvitiligo phenotype in to date unaffected persons. Preferably, suchunaffected persons are persons with higher risk of vitiligo; i.e.persons with a family history of vitiligo.

Pharmaceutical Compositions Pharmaceutically Acceptable Salts

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the acetate derived from acetic acid, the aconate derived fromaconitic acid, the ascorbate derived from ascorbic acid, thebenzenesulfonate derived from benzensulfonic acid, the benzoate derivedfrom benzoic acid, the cinnamate derived from cinnamic acid, the citratederived from citric acid, the embonate derived from embonic acid, theenantate derived from enanthic acid, the formate derived from formicacid, the fumarate derived from fumaric acid, the glutamate derived fromglutamic acid, the glycolate derived from glycolic acid, thehydrochloride derived from hydrochloric acid, the hydrobromide derivedfrom hydrobromic acid, the lactate derived from lactic acid, the maleatederived from maleic acid, the malonate derived from malonic acid, themandelate derived from mandelic acid, the methanesulfonate derived frommethane sulphonic acid, the naphthalene-2-sulphonate derived fromnaphtalene-2-sulphonic acid, the nitrate derived from nitric acid, theperchlorate derived from perchloric acid, the phosphate derived fromphosphoric acid, the phthalate derived from phthalic acid, thesalicylate derived from salicylic acid, the sorbate derived from sorbicacid, the stearate derived from stearic acid, the succinate derived fromsuccinic acid, the sulphate derived from sulphuric acid, the tartratederived from tartaric acid, the toluene-p-sulphonate derived fromp-toluene sulphonic acid, and the like. Such salts may be formed byprocedures well known and described in the art.

Other acids such as oxalic acid, which may not be consideredpharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining a chemical compound of theinvention and its pharmaceutically acceptable acid addition salt.

In another embodiment, the compounds of the invention are used in itsfree base form according to the present invention.

Metal salts of a chemical compound of the invention include alkali metalsalts, such as the sodium salt of a chemical compound of the inventioncontaining a carboxy group.

The chemical compounds of the invention may be provided in unsolvated orsolvated forms together with a pharmaceutically acceptable solvents suchas water, ethanol, and the like. Solvated forms may also includehydrated forms such as the monohydrate, the dihydrate, the hemihydrate,the trihydrate, the tetrahydrate, and the like. In general, solvatedforms are considered equivalent to unsolvated forms for the purposes ofthis invention.

Administration and Formulation

The production of medicaments containing the PDE5 inhibitors of theinvention, its active metabolites or isomers and salts according to theinvention and their application can be performed according to well-knownpharmaceutical methods.

While the PDE5 inhibitors of the invention useable according to theinvention for use in therapy may be administered in the form of the rawchemical compound, it is preferred to introduce the active ingredient,optionally in the form of a physiologically acceptable salt in apharmaceutical composition together with one or more adjuvants,excipients, carriers, buffers, diluents, and/or other customarypharmaceutical auxiliaries. Such salts of the PDE5 inhibitors of theinvention may be anhydrous or solvated.

In a preferred embodiment, the invention provides medicaments comprisinga compound useable according to the invention, or a pharmaceuticallyacceptable salt or derivative thereof, together with one or morepharmaceutically acceptable carriers therefor, and, optionally, othertherapeutic and/or prophylactic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not harmful to the recipient thereof.

A medicament of the invention may be those suitable for oral, rectal,bronchial, nasal, topical, buccal, sub-lingual, transdermal, vaginal orparenteral (including cutaneous, subcutaneous, intramuscular,intraperitoneal, intravenous, intraarterial, intracerebral, intraocularinjection or infusion) administration, or those in a form suitable foradministration by inhalation or insufflation, including powders andliquid aerosol administration, or by sustained release systems. Suitableexamples of sustained release systems include semipermeable matrices ofsolid hydrophobic polymers containing the compound of the invention,which matrices may be in form of shaped articles, e.g. films ormicrocapsules.

The compounds useable according to the invention, together with aconventional adjuvant, carrier, or diluent, may thus be placed into theform of medicament and unit dosages thereof. Such forms include solids,and in particular tablets, filled capsules, powder and pellet forms, andliquids, in particular aqueous or non-aqueous solutions, suspensions,emulsions, elixirs, and capsules filled with the same, all for oral use,suppositories for rectal administration, and sterile injectablesolutions for parenteral use. Such medicament and unit dosage formsthereof may comprise conventional ingredients in conventionalproportions, with or without additional active compounds or principles,and such unit dosage forms may contain any suitable effective amount ofthe active ingredient commensurate with the intended daily dosage rangeto be employed.

The compound useable according to the invention can be administered in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise,as the active component, either a compounds useable according to theinvention or a pharmaceutically acceptable salt of a compounds useableaccording to the invention.

For preparing a medicament from a compound useable according to theinvention, pharmaceutically acceptable carriers can be either solid orliquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier can be one or more substances which may also act as diluents,flavouring agents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingcapacity in suitable proportions and compacted in the shape and sizedesired. Suitable carriers are magnesium carbonate, magnesium stearate,talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoabutter, and the like. The term “preparation” is intended to include theformulation of the active compound with encapsulating material ascarrier providing a capsule in which the active component, with orwithout carriers, is surrounded by a carrier, which is thus inassociation with it. Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets, and lozenges can be used assolid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glyceride or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify. Compositions suitable for vaginaladministration may be presented as pessaries, tampons, creams, gels,pastes, foams or sprays containing in addition to the active ingredientsuch carriers as are known in the art to be appropriate. Liquidpreparations include solutions, suspensions, and emulsions, for example,water or water-propylene glycol solutions. For example, parenteralinjection liquid preparations can be formulated as solutions in aqueouspolyethylene glycol solution.

The chemical compound according to the present invention may thus beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilisers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

In one embodiment of the present invention, the medicament is appliedtopically or systemically or via a combination of the two routes.

In an especially preferred embodiment of the present invention themedicament is applied topically. This reduces possible side effects andlimits the necessary treatment to those areas affected.

Preferably the medicament is prepared in form of an ointment, a gel, aplaster, an emulsion, a lotion, a foam, a cream, a cream of a mixedphase or amphiphilic emulsion system (oil/water-water/oil mixed phase),a liposome, a transfersome, a paste or a powder.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilisingagents, dispersing agents, suspending agents, thickening agents, orcolouring agents.

For topical administration, the compounds of the present invention maybe administered in a formulation containing 0.001% to 10% per weight ofthe compound, preferably between 0.01% to 10% per weight of thecompound, even more preferred between 0.1% and 5% per weight of thecompound.

Especially preferred are topical formulations of compounds of theinvention, especially of Tadalafil and Sildenafil and salts and hydratesthereof, especially in an O/W emulsion (oil-in-water emulsion) or cream.The invention thus also relates to a composition suitable for topicaluse, comprising a compound of the invention, especially selected fromTadalafil and Sildenafil or a pharmaceutically acceptable salt thereof.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerol or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomising spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form. Tablets or capsules for oral administration andliquids for intravenous administration and continuous infusion arepreferred compositions.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co. Easton, Pa.).

In another aspect the present invention relates to a compositioncomprising a PDE 5 inhibitor useable according to the invention or anisomer thereof, or a pharmaceutically acceptable salt thereof, and oneor more further active ingredients which are known to be suitable forthe treatment and/or prevention of hypopigmentary disorders, especiallyvitiligo. Especially preferred active ingredients which can be used incombination with the compounds of the invention are Calcineurininhibitors, for example Cyclosporin A, Cyclosporin G, Cyclosporin B,Cyclosporin C, Cyclosporin D, Dihydro-cyclosporin D, Cyclosporin E,Cyclosporin F, Cyclosporin H, Cyclosporin I, ASM-240, Pimecrolimus,Tacrolimus, 13-Desmethyl-derivatives of Tacrolimus (L-685487), L-683519and/or 17-Ethyl-derivatives of Tacrolimus, preferably Pimecrolimus,Tacrolimus, or Cyclosporin A, especially preferably Tacrolimus, steroid,for example Betamethasone, Betamethasone-17-valerate, Fluocinolone,Triamcinolone, Triamcinolone acetonide, clobetasol, clobetasolpropionate, halobetasol, hydrocortisone, cortisone, desonide,Prednisolone, paramethasone, Methylprednisolone, Dexamethasone,Deflazacort, Vitamin D analogues, especially calcipotriol,Pseudocatalase, or other active ingredients which were suggested forvitiligo treatment like levamisole, Fluorouracil, alpha-MSH,Clofazimine, Thiambutosine BP, Chloroquine, Penicillamine, Tar,Minoxidil, Inosiplex, Mechlorethamine, Cyclophosphamide, Anapsos,Antioxidants like Gingko biloba, Canthaxanthine, beta-carotene,alpha-Tocopherol, combination of alpha-Tocopherol, ubiquinone,seleno-methionine and methionine, Pentoxifylline, vitamins and traceelements, like Vitamin B12, folic acid, vitamin C, vitamin E, coppersalts, human placental extract, khellin and phenylalanine.

In an especially preferred embodiment, a PDE 5 inhibitor useableaccording to the invention or an isomer thereof, or a pharmaceuticallyacceptable salt thereof are combined with a compound selected from thegroup of Pimecrolimus, Tacrolimus, and Cyclosporin A. Especiallypreferred are combinations of a PDE5 inhibitor selected from Tadalafiland Sildenafil or a pharmaceutically acceptable salt thereof and acompound selected from the group of Pimecrolimus, Tacrolimus, andCyclosporin A.

In another embodiment, the invention relates to the use of one of theabove-mentioned compositions for the manufacture of a medicament for thetreatment and/or prevention of hypopigmentary disorders, especiallyvitiligo. The same administration forms as discussed above for PDE 5inhibitors useable according to the invention or an isomer thereof or apharmaceutically acceptable salt thereof alone, are suitable for thecompositions, especially the topical application on lesions fortreatment, or on unaffected skin for prevention. In another aspect ofthe present invention, the active ingredients are administered togetheror spatially and/or temporally separated.

In another aspect the present invention relates to treatments forhypopigmentary disorders, especially vitiligo comprising administrationof a medicament containing PDE 5 inhibitors useable according to theinvention or an isomer thereof, or a pharmaceutically acceptable saltthereof alone and administration of one or more further treatment formswhich are known to be suitable for the treatment and/or prevention ofvitiligo. Preferred treatment forms which can be combined with thetreatment with a medicament containing PDE 5 inhibitors useableaccording to the invention or an isomer thereof, or a pharmaceuticallyacceptable salt thereof alone, and optionally other active substances,are PUVA treatment, KUVA treatment, heliotherapy, climatotherapy,especially at the Dead Sea, Laser therapy, for example low energy lasertherapy, ultrapulse carbondioxide laser therapy, short pulsecarbondioxide laser therapy or Ruby laser therapy, surgical therapieslike minigraft, suction epidermal grafting, dermo-epidermal grafts,epidermal suspensions, in vivo cultured epidermis and melanocytesuspensions, or UVB treatment.

Assays for Testing Subject Compounds

In general, tests for measuring the effect on hypopigmentary disordersare described in the prior art. For example, an in vitro modelconsisting of keratinocytes and melanocytes may be used. E.g. thecommercially available MelanoDerm Skin Model (MatTek Corporation,Ashland, Mass.) uses NHEK (normal human derived keratinocytes)-NHEM(normal human derived melanocytes) co-cultures (MelanoDerm Skin model)to model the human epidermis taking into account that melanocytes aredependent on keratinocyte signalling. NHEKs are cultivated in cultureinserts placed on the NHEM monolayers according to the instructions ofthe manufacturer (MatTek Corporation, Ashland, Mass.). NHEMs undergospontaneously melanogenesis up to 3 weeks of culturing. Regardingevaluation of pharmaceutical agents to stimulate skin pigmentation asneeded for treating hypopigmentary disorders, the tissues darken fasterthan untreated controls.

Other in vitro assays for determining the effect of a subject compoundon hypopigmentary disorders are in vitro assays based on melanin contentanalysis.

Melanin content analysis assays are also described in the prior art.

For example, treated and control melanocytes are harvested bytrypsinization. Ten percent of the melanocytes are removed and countedon a Coulter counter. The remaining melanocytes are centrifuged and theresulting cell pellet is washed in phosphate-buffered saline pH 7.4 andre-centrifuged. The cell pellet is then dissolved in 1 ml of 1 M sodiumhydroxide. The optical density of this solution is measuredspectrophotometrically at 405 nm and is compared to synthetic melanin todetermine melanin content per cell. A higher melanin content reflectsenhanced pigmentation.

Similarly, the assay can be performed as follows: treated and controlmelanocytes are harvested by trypsinization, washed withphosphate-buffered saline (PBS), suspended in 500 μl PBS, and counted.The cells are then solubilized by adding 500 μl of 10N NaOH andincubating for 30 min at room temperature. Absorbance at 475 nm ismeasured and compared with a standard curve for synthetic melanin.

Alternatively, the ¹⁴C-tyrosine melanin-formation assay can be used,which measures the radioactive melanin formed when ¹⁴C-tyrosine isconverted to the acid-insoluble melanin biopolymer. For this assay, cellextracts from treated and control cells are incubated with ¹⁴C-tyrosinefor 1 hour and absorbed on filter paper. The filter paper is dried thenwashed in 0.1 mol/L hydrochloric acid three times and placed in ascintillation vial with 5 ml scintillator solution. The radioactivity iscounted in triplicate using the same scintillator counter.

Alternatively, the effect of a compound on a hypopigmentary disorder canbe determined by measuring tyrosinase activity, which are well describedin the prior art.

For example, tyrosinase activity of cell culture can be determined:treated and control melanocytes are incubated with 1.0 μCi [³H]tyrosineper ml. 700 μl of 10% trichloroacetic acid containing 20% charcoal(charcoal solution) is added to the medium (700 μl), and the mixture ismixed in a vortex for 30 s and then centrifuged at 10,000 rpm for 10min. Seven hundred microliters of the supernatant is transferred into anew tube and treated twice with the charcoal solution. The radioactivityof the final supernatant is determined in a liquid scintillationcounter.

Alternatively, tyrosinase activity can be determined in cell extracts.For example, treated and control melanocytes are collected and washedtwice with PBS, and then lyzed in 0.1 M sodium phosphate buffer (pH 6.8)containing 1% Triton X-100. After determining the protein content in thecell extract, 10 μg of each extract is incubated in 100 μl of 100 mMsodium phosphate buffer (pH 6.8) containing 1.0 μCi [³H]tyrosine per ml,5 μg L-dihydroxyphenylalanine, and 1% Triton X-100 for 15 min at 37° C.After adding 900 μl of charcoal solution, the samples stand for 20 minat 4° C. and then are centrifuged at 10,000 rpm for 10 min. Thesupernatants are applied to a 0.2 ml Dowex-50 column equilibrated in 10%trichloroacetic acid and washed with 0.5 ml of 10% trichloroacetic acid,after which the radioactivity of the effluents is determined in theliquid scintillation counter.

Also, some animal models of varying predictability and suitabilityexist. An evaluation of suitability of various vitiligo animal models isdescribed in Vitiligo (eds. S. Hann and J. J. Nordlund, BlackwellScience, Chapter 33: Animal models by L. Lamoreux and R. E. Boissy)

For example, the Smyth chicken exhibiting a genetically inherited formof vitiligo-like depigmentation resulting from the loss of melanocytesin feathers is discussed as vitiligo model. The pigmentation phenotypeof this animal model appears to involve an immune response. Also, theso-called vitiligo mouse is described. In this model no immune componentis involved and the disorder is not polyfactorial; i.e. unlike inhumans.

Vitiligo, for example, is not a simple, one-locus-disease, andinheritance is not its only cause. Therefore, in the case of vitiligo,animal models must be used with the knowledge that the disorder observedin the genetically defective animal will not be homologous with thedisorder of the average human vitiligo patient. Thus, the study of oneanimal model, especially if the defect is caused by one gene locus inthe model, need not be more predictive than an in vitro model.

None of the aforementioned tests has proved particular useful on its ownwhen it came to identifying compounds useful in the treatment and/orprevention of hypopigmentary disorders, given that not many compoundsare known to have a pronounced positive effect on the onset ofhypopigmentary disorders. This shortcoming of the prior art has now beenovercome, in that the present inventors have found that surprisingly PDE5 inhibitors useable according to the invention or an isomer thereof, ora pharmaceutically acceptable salt thereof, as defined before, providefor compounds which have a beneficial effect on hypopigmentarydisorders, especially on vitiligo. Therefore, according to anotheraspect of the present invention, it provides for the use of PDE 5inhibitors useable according to the invention or an isomer thereof, or apharmaceutically acceptable salt thereof, as defined above, in ascreening assay for compounds which are suitable for the treatmentand/or prevention of hypopigmentary disorders. In one embodiment, suchscreening assay is an in-vitro-model consisting of a co-culture ofkeratinocytes and melanocytes as described above. In another embodimentthe screening assay is an in-vitro-assay based on melanin contentanalysis, as described above. In another embodiment, the screening assayis based on the measurement of tyrosinase activity, as described above.In yet another embodiment, the screening assay is based on an animalmodel, as described above.

In all these screening assays the PDE 5 inhibitors useable according tothe invention or an isomer thereof, or a pharmaceutically acceptablesalt thereof serve as positive controls in that they inhibit/prevent theonset of hypopigmentary disorders, especially vitiligo and the responseof the assay system towards these controls is compared with the responseof the assay system towards a subject compound to be tested.

FIG. 1 shows the influence of Sildenafil on dendrite formation inmelanocytes in a melanocyte dendrite outgrowth assay described below.Positive control is IBMX i.e. 3-isobutyl-1-methylxanthin, a compoundknown to increase melanocyte dendricity. The dendricity of untreatedmelanocytes was set as 1 in each experiment.

EXAMPLES Example 1 Effect of Sildenafil on Melanocyte Function

A possibility to test the effect of a compound on melanocyte function asa measure for pigmentation, the melanocyte dendrite outgrowth assay canbe performed. Vitiligo melanocytes for example have only stubbydendrites. Increasing dendricity as a prerequisite for the transfer ofthe melanosomes from melanocytes to the surrounding keratinocytesrescues this defect.

For this assay, cells from a human melanoma cell line (Mel-Ho) wereobtained from DSMZ (Deutsche Sammlung für Mikroorganismen andZellkulturen) and were cultured according to the protocol provided byDSMZ. In short, after thawing the melanocytes were cultured in T-75flasks in melanocyte culture media (provided by the manufacturer) untilthey reach 70-80% confluency. The melanocytes were then trypsinized,transferred into 5-10 new T-75 flasks, and grown again to sameconfluency as described above. After this expansion step the melanocyteswere immediately used for the Melanocyte Dendrite Outgrowth Assay orwere frozen for later use.

For the assay, the melanocytes were seeded in 24 well plates at adensity of 1-5×10⁴ cells/well. After 24 hours, the melanocytes weretreated with 100 μM IBMX (Sigma-Aldrich) or different concentrations ofSildenafil and Tadalafil for 24 hours. IBMX(=3-isobutyl-1-methylxanthin) is known to cause increased melanocytedendricity and was used as a positive control. Cells treated with mediaonly were used as a negative control. Melanocyte dendrite outgrowth wasdocumented by digital photography (Canon G2 Powershot) after 3, 6 and 24hours. In addition, melanocyte dendricity was scored by 3 blindedindividuals after 24 hours. The score ranges from 1 to 4; 1 representingmelanocytes with no dendrites and 4 representing melanocytes with manylong and branched dendrites. The scoring result of 3 individualexperiments performed with Sildenafil is shown in FIG. 1. FIG. 1 showsthe negative control treated with media only, exhibiting a score of 1,whereas in the positive control, i.e. IBMX-treated cells, the scorereached >3. Surprisingly it was found that also Sildenafil-treatedcells, dendricity was strongly stimulated (score >3). 10 μM Sildenafilwas used to obtain an score of >3, however also lower concentrations(down to 10 nM) of Sildenafil was sufficient to induce dendriteformation.

Example 2 Effect of Tadalafil on Melanocyte Function

The experiment was performed as described in Example 1, however usingTadalafil as active component.

The results obtained for Tadalafil were very similar to the resultsobtained with Sildenafil.

It was found that also Tadalafil effectively induces dendricity inmelanocytes which proves good suitability of the compounds useableaccording to the invention for treating and/or preventing hypopigmentarydisorders, especially vitiligo.

In summary, the strongly increased dendricity induced by Sildenafil andTadalafil proves good suitability of the compounds useable according tothe invention for treating and/or preventing hypopigmentary disorders,especially vitiligo.

Example 3 Effect of PDE5 Inhibitors on Pigmentation In Vitro

In order to test the effect of PDE5 inhibitors on pigmentation, an invitro model consisting of keratinocytes and melanocytes is used, namelythe commercially available MelanoDerm Skin Model (MatTek Corporation,Ashland, Mass.). This model uses NHEK (normal human derivedkeratinocytes)-NHEM (normal human derived melanocytes) co-cultures(MelanoDerm Skin model) to model the human epidermis taking into accountthat melanocytes are dependent on keratinocyte signalling. NHEKs arecultivated in culture inserts placed on the NHEM monolayers according tothe instructions of the manufacturer (MatTek Corporation, Ashland,Mass.). NHEMs undergo spontaneously melanogenesis up to 3 weeks ofculturing. Regarding evaluation of pharmaceutical agents to stimulateskin pigmentation as needed for treating hypopigmentary disorders, thetissues darken faster than untreated controls. It is expected that bothSildenafil and Tadalafil induce pigmentation in that model compared tothe negative controls.

1. A method of treating hypopigmentary diseases or disorders comprisingadministering a PDE5 inhibitor to a patient suffering from ahypopigmentary disease or disorder, wherein said PDE5 inhibitor isselected from tadalafil and pharmaceutically acceptable salts thereof,and wherein said hypopigmentary disease or disorder is vitiligo.
 2. Themethod according to claim 1, wherein said PDE5 inhibitor is a compoundaccording to formula (II):

or an isomer thereof, or a pharmaceutically acceptable salt thereof. 3.The method according to claim 1, further comprising administering saidPDE5 inhibitor topically or systemically or via a combination thereof.4. The method according to claim 3, further comprising administeringsaid PDE5 inhibitor in the form of a medicament that is in the form ofan ointment, a gel, a plaster, an emulsion, a lotion, a foam, a cream ofa mixed phase or amphiphilic emulsion system, a liposome, atransfersome, a paste or a powder, or a solution or suspension.
 5. Acomposition comprising tadalafil or a pharmaceutically acceptable saltthereof and one or more further active ingredients suitable for thetreatment and/or prevention of hypopigmentary disorders.
 6. Thecomposition according to claim 5, further comprising at least one activeingredient selected from the group consisting of cyclosporin A,cyclosporin G, cyclosporin B, cyclosporin C, cyclosporin D,dihydro-cyclosporin D, cyclosporin E, cyclosporin F, cyclosporin H,cyclosporin I, ASM-240, pimecrolimus, tacrolimus,13-desmethyl-derivatives of tacrolimus (L-685487), L-683519 and/or17-ethyl-derivatives of tacrolimus; steroids; vitamin D analogues;pseudocatalase; levamisole, fluorouracil; alpha-MSH; clofazimine;thiambutosine BP; chloroquine; penicillamine; tar; minoxidil; inosiplex;mechlorethamine; cyclophosphamide; anapsos; antioxidants;pentoxifylline; vitamins and trace elements. vitamin B12, folic acid,vitamin C, vitamin E, copper salts, human placental extract, khellin andphenylalanine.
 7. The composition according to claim 5, wherein saidcomposition is formulated for topical use.
 8. The composition accordingto claim 6 wherein said 17-ethyl-derivatives of tacrolimus comprisespimecrolimus, tacrolimus, or cyclosporin A.
 9. The composition accordingto claim 6 wherein said steroids comprises betamethasone,betamethasone-17-valerate, fluocinolone, triamcinolone, triamcinoloneacetonide, clobetasol, clobetasol propionate, halobetasol,hydrocortisone, cortisone, desonide, prednisolone, paramethasone,methylprednisolone, dexamethasone or deflazacort.
 10. The compositionaccording to claim 6 wherein said vitamin D analogues comprisescalcipotriol.
 11. The composition according to claim 6 wherein saidantioxidants comprises Gingko biloba, canthaxanthine, beta-carotene,alpha-tocopherol, a combination of alpha-tocopherol ubiquinoneseleno-methionine or methionine.
 12. The composition according to claim6 wherein said vitamins or trace elements comprises vitamin B12, folicacid, vitamin C, vitamin E, copper salts, human placental extract,khellin and phenylalanine.
 13. A method of treating or preventinghypopigmentary disorders comprising administering a compositionaccording to claim 5 to a patient suffering from a hypopigmentarydisorder.